The proposed work in this shared instrumentation grant application comes from many of the clinical and/or translational research programs ongoing at the Cleveland Clinic, a major research institution in the northeast Ohio region. The purpose of this application is to seek funding to purchase a next generation sequencer, the Illumina Genome Analyzer IIx. All but one of the major users is NIH/NCI funded by a variety of mechanisms (R01, P01, U54, etc). The Genome Analyzer has the power and flexibility to enable a wide range of genome-scale applications. The instrument is a direct consequence of the NIH initiative for the $1000 genome and represents the first generation of such technologies to come to the market. The underlying technology can be summarized as massive parallel sequencing (creating 2-4 GB of sequence in a typical 3-5 day run). As detailed in the application, the supported projects primarily include biomarker discovery and clinical/translational sciences studies, representing the unique strengths in our institution and taking advantage of all current applications of the next generation sequencers: 1) digital gene expression profiling: better dynamic range than micro-array based profiling and reliable detection of low-abundance transcripts, 2) ChIP-seq: genome wide profiles of DNA-protein interaction and of epigenetic regulation in translational research programs related to human disease, 3) small or non-coding RNA discovery and 4) genome sequencing: re- sequencing of large genomic regions in patient DNA to uncover disease causing mutations. The acquisition of the Genome Analyzer, with its scale and value, are essential in lifting the currently NIH-funded projects and many other new projects to the next higher level of translational sciences in northeast Ohio. Cleveland Clinic has already committed substantial resources to the development of translational genomics and genomic medicine, including the founding of its Genomic Medicine Institute with a new Genomics Core Facility, personnel to oversee operations and a fiscal plan to ensure its operation and maintenance for the long-term.